Sickle cell disease (SCO) is a common disorder among African-Americans and other minority populations. Approximately 70,000 Americans are affected by the disease. SCO is characterized by chronic anemia and unpredictable bouts of severe pain, often called a painful "crisis". The classical "vaso-occlusive" theory of acute sickle cell pain does not explain all its clinical features. Further, the current treatment of acute sickle cell pain is inadequate. The basic cause of this pain needs to be understood to permit the development of better, specific treatments. We will explore two novel potential mechanisms of sickle pain: acute bone turnover and disordered porphyrin metabolism. The results of this study could change the way we think about and treat the acute painful crisis of SCO. The broad, long-term objectives of this application are to fully understand the causes of acute sickle cell pain and to develop new, targeted treatments. The specific aims of this project are: (1) To compare the concentrations of serum and urinary markers of bone resorption obtained during an acute painful episode to the concentrations obtained after the episode has resolved;(2) to compare the concentrations of urinary and blood porphyrins during an acute painful episode to the concentrations obtained after the episode has resolved;(3) to determine whether abnormalities on MR imaging consistent with ischemia or necrosis can be found at sites of pain;and (4) to explore the associations between the primary site of pain (e.g. abdominal versus extremity pain) and the relative concentrations of porphyrins or markers of bone resorption. To achieve these aims we will conduct an observational study with repeated clinical, laboratory, and readiographic measures over the time-course of a painful episode. We will perform an analysis of matched pairs, in which each patient serves as his or her own control. The Southwestern Comprehensive Sickle Cell Center has the expertise and resources to conduct this proposed inter-center investigation. The pilot data generated by this study are needed because there are no available estimates of the magnitude and variability of these metabolic markers during and after painful episodes. The results of this pilot study will provide the data needed to design definitive, observational studies and novel intervention trials.